Falciparum malaria remains one of the most important infectious diseases in the world, and the problem is greatest in children and pregnant women in Africa. Among key tools to control and eventually eliminate malaria is intermittent preventive therapy (IPT), the provision of full treatment courses at regular intervals to high risk groups. In Africa, IPT is severely compromised by drug resistance. For treatment of falciparum malaria, older regimens have been replaced by artemisinin-based combination therapies (ACTs). For IPT, a similar change is warranted, and the logical choice is dihydroartemisinin/piperaquine (DHA/PQ), which benefits from rapid killing of most parasites by DHA and protection for weeks after therapy due to the long half-life of PQ. We are now beginning a trial in Uganda that will explore the preventive efficacy and impacts on immune responses of monthly DHA/PQ administered during pregnancy and to infants. We expect that DHA/PQ will offer good preventive efficacy. However, the success of DHA/PQ for IPT is challenged by 3 concerns. First, the pharmacokinetics (PKs) of the regimen, in particular PQ, is not well characterized, especially in pregnant women and young children, and also in the context of IPT. Improved understanding is critical, as available evidence suggests that DHA/PQ is not adequately dosed in young children, and guidelines for pregnancy are lacking. Second, the pharmacodynamics of DHA/PQ are uncertain. What dosing regimens will maximize antimalarial preventive efficacy in target populations? Third, resistance to DHA is spreading in Southeast Asia, and of more immediate concern is resistance to PQ. We describe experiments to better characterize the PKs of DHA/PQ in pregnant women and young children receiving IPT and to characterize associations between exposure to DHA/PQ and risks of malaria and of selection of drug resistance. We hypothesize a) that the PKs of the components of DHA/PQ differ between our target populations and non-pregnant adults, b) that a threshold concentration of PQ will be associated with protection against malaria, and c) that a second lower threshold will define concentrations of PQ that permit malaria infection but select for drug resistant parasites. To test these hypotheses, we will leverage our outstanding infrastructure for malaria research in Tororo, Uganda and link with our funded trial that will assess the preventive efficacy of DHA/PQ. We will add to the trial studies to improve our understanding of the full impact of DHA/PQ, the most important new regimen for the prevention of malaria. Our specific aims will be (1) to define the PKs of DHA/PQ when used as IPT for Ugandan pregnant women and children, (2) to characterize associations between exposure to PQ and circulating parasitemia, placental malaria, and clinical malaria in pregnant women and children, and (3) to characterize associations between exposure to DHA and PQ and risk of altered drug sensitivity. Overall, our primary goal will be to optimize dosing regimens for IPT with DHA/PQ in pregnant women and children to enable protection against malaria without selection of drug resistance.